This invention relates to the treatment of brain tumours using gene therapy.
The treatment of malignant glioma continues to challenge physicians and scientists. Thymidine kinase gene therapy, using the Herpes Simplex virus thymidine kinase (HSVtk) gene, is one of the most promising treatment modalities, in attempts to change the survival of malignant glioma patients. HSVtk gene therapy is based on the ability of thymidine kinase to catalyze the phosphorylation of ganciclovir (GCV). Phosphorylated GCV acts as a toxic nucleotide analogue, leading to the death of the target cells. This phenomenon is further enhanced by a bystander effect, where neighbouring cells are also destroyed even without transfection. This effect is thought to be due to the release of toxic nucleotide analogues from the transfected cells to neighbouring cells via gap junctions.
Retroviruses and adenoviruses have been used as vectors for gene therapy. Both vectors have certain advantages and limitations. Brain tumours are especially suitable for retrovirus-mediated gene transfer, since retroviruses can only infect proliferating cells while normal, non-dividing brain tissue remains intact. The gene transfer efficiency of retroviruses is relatively low, but could be improved by using retrovirus packaging cells instead of isolated viruses. The transduction time can theoretically be prolonged and the number of transfected cells increased. With retroviruses, the transfected gene incorporates into the genome of the target cell and therefore long-term gene expression can be achieved.
The present invention is based on the surprising finding that treatment of brain tumours using thymidine kinase gene therapy can be accomplished more effectively if an adenovirus is used as the vehicle to transfer the gene into tumour cells.
According to the present invention, an adenovirus comprises a gene encoding thymidine kinase, and medicaments containing it, are useful for treating a brain tumour. In particular, the tumour is treated following administration of gangciclovir or an equivalent compound.
The thymidine kinase gene will typically be that derived from the Herpes Simplex virus (HSVtk).
The adenovirus/thymidine kinase gene construct is shown to be more beneficial than retrovirus gene transfer.
A construct of the invention can be used to treat a tumour. Treatment may comprise the steps of:
(i) administering an adenovirus comprising a gene encoding a thymidine kinase, into the wall of the tumour cavity; and
(ii) administering a compound that forms a cytotoxic compound when phosphorylated.
The compound used in step (ii) may be ganciclovir or a derivative thereof. This method may be used to treat any tumour, preferably a brain tumour, e.g. a malignant glioma. The composition used in step (i) may be administered repeatedly, preferably in 40 to 80 separate applications.
The composition used in the present invention is preferably formulated without the addition of proteins (other than those associated with the adenovirus). This is believed to be preferable to those compositions where albumin is added to reduce the effects of degradative enzymes on the active components. Preferably, this composition comprises glycerol as a stabiliser.
The amount of active products that should be administered to a patient, in use of the invention, can be determined by those skilled in the art, based on information provided herein and on the usual considerations such as the route of administration, the condition being treated and its status, etc.
The following Example illustrates the invention.